Engineering the composition of thymic stroma to improve transplant tolerance induction 4495

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Abstract Description Transplant recipients are put on life-long immunosuppression, experiencing side effects and incomplete control of rejection. Among alternative immunotherapies, bone marrow transplantation has shown the most promise, but remains limited in its clinical application. Its therapeutic efficacy relies prominently on altering negative selection of developing T cells in the thymus via colonization by hematopoietic cells. By shifting focus to the stromal population of thymic epithelial cells (TEC), we hypothesize that engrafting donor-matched TEC could provide an effective and complementary process of thymocytes selection in favor of donor MHCs and antigens. We developed an approach to achieve lasting engraftment of congenic and allogenic TEC into a recipient’s thymus. We used MHCII KO B6 mice, which lack CD4 T cells, to assess TEC’s capacity to select alloreactive cells. Following intra-thymic injection of either B6 or B6 x Balb/c TEC, CD4 T cells appear in both the thymus and periphery, with Treg:TH ratios comparable to wildtype controls. Mixed leukocyte reactions showed that donor-selected CD4 T cells are functional and proliferate as a function of the selecting MHC. We are currently performing skin transplants to assess the in vivo function and graft-protective effect of our donor-selected T cells. Our results highlight TEC as a potential tool to promote transplant tolerance through targeted thymic education. Funding Sources Supported by DoD W81XWH2210976 Topic Categories Transplantation Immunology (TRAN)

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